Compositions and methods for repair of aneurysms are described. In particular, embolic devices that allow the operator to deliver and transform in situ embolic material.
An aneurysm is a dilation of a blood vessel (similar to a balloon) that poses a risk to health from the potential for rupture, clotting, or dissecting. Rupture of an aneurysm in the brain causes stroke, and rupture of an aneurysm in the abdomen causes shock. Cerebral aneurysms are usually detected in patients as the result of a seizure or hemorrhage and can result in significant morbidity or mortality.
There are a variety of materials and devices which have been used for treatment of aneurysms, including platinum and stainless steel microcoils, polyvinyl alcohol sponges (Ivalone), and other mechanical devices. For example, vaso-occlusion devices are surgical implements or implants that are placed within the vasculature of the human body, typically via a catheter, either to block the flow of blood through a vessel making up that portion of the vasculature through the formation of an embolus or to form such an embolus within an aneurysm stemming from the vessel. One widely used vaso-occlusive device is a helical wire coil having windings which may be dimensioned to engage the walls of the vessels. (See, e.g., U.S. Pat. No. 4,994,069 to Ritchart et al.) Other less stiff helically coiled devices have been described, as well as those involving woven braids.
U.S. Pat. No. 5,354,295 and its parent, U.S. Pat. No. 5,122,136, both to Guglielmi et al., describe an electrolytically detachable embolic device. Modified GDC coils have also been used in aneurysms, for example surface-modified GDCs as described in Murayama et al. (1999) American J Neuradiol 20(10):1992-1999. Vaso-occlusive coils having little or no inherent secondary shape have also been described. For instance, coowned U.S. Pat. No. 5,690,666 and 5,826,587 by Berenstein et al., describes coils having little or no shape after introduction into the vascular space.
A variety of mechanically detachable devices are also known. For instance, U.S. Pat. No. 5,234,437, to Sepetka, shows a method of unscrewing a helically wound coil from a pusher having interlocking surfaces. U.S. Pat. No. 5,250,071, to Palermo, shows an embolic coil assembly using interlocking clasps mounted both on the pusher and on the embolic coil. U.S. Pat. No. 5,261,916, to Engelson, shows a detachable pusher-vasoocclusive coil assembly having an interlocking ball and keyway-type coupling. U.S. Pat. No. 5,304,195, to Twyford et al., shows a pusher-vaso-occlusive coil assembly having an affixed, proximally extending wire carrying a ball on its proximal end and a pusher having a similar end. The two ends are interlocked and disengage when expelled from the distal tip of the catheter. U.S. Pat. No. 5,312,415, to Palermo, also shows a method for discharging numerous coils from a single pusher by use of a guidewire which has a section capable of interconnecting with the interior of the helically wound coil. U.S. Pat. No. 5,350,397, to Palermo et al., shows a pusher having a throat at its distal end and a pusher through its axis. The pusher sheath will hold onto the end of an embolic coil and will then be released upon pushing the axially placed pusher wire against the member found on the proximal end of the vaso-occlusive coil.
In addition, several patents describe deployable vaso-occlusive devices that have added materials designed to increase their thrombogenicity. For example,. fibered vasoocclusive devices have been described at a variety of patents assigned to Target Therapeutics, Inc., of Fremont, Calif. Such vaso-occlusive coils having attached fibers is shown in U.S. Pat. Nos. 5,226,911 and 5,304,194, both to Chee et al. Another vasoocclusive coil having attached fibrous materials is found in U.S. Pat. No. 5,382,259, to Phelps et al. The Phelps et al. patent describes a vaso-occlusive coil which is covered with a polymeric fibrous braid on its exterior surface. U.S. Pat. No. 5,658,308 to Snyder is directed to a coil having a bioactive core. The coils may be coated with agarose, collagen or sugar. U.S. Pat. No. 5,669,931 to Kupiecki discloses coils that may be filed or coated with thrombotic or medicinal material. U.S. Pat. No. 5,749,894 to Engleson discloses polymer coated vaso-occlusion devices. U.S. Pat. No. 5,690,671 to McGurk discloses an embolic element which may include a coating, such as collagen, on the filament surface.
U.S. Pat. No. 5,536,274 to Neuss shows a spiral implant which may assume a variety of secondary shapes. Some complex shapes can be formed by interconnecting two or more of the spiral-shaped implants. To promote blood coagulation, the implants may be coated with metal particles, silicone, PTFE, rubber latices, or polymers. U.S. Patent No. 5,980,550 describes a vaso-occlusive device having a bioactive inner coating and a water-soluble outer coating. Co-owned WO/027445, titled xe2x80x9cBioactive Coating for Vaso-occlusive Devices,xe2x80x9d describes vaso-occlusive devices coated with a collagen-based material and, additionally, describes the use of a tie-layer between the device and the collagen-based coating.
Liquid embolics, such as cyanoacrylate glues and fibrin sealants, have also been used in animal and human subjects. See, e.g., Interventional Radiology, Dandlinger et al, ed., Thieme, N.Y., 1990:295-313; Suga et al. (1992) No Shinkei Geka 20(8):865-873; Moringlane et al. (1987) Surg Neurol 28(5):361-366; Moringlane et al. (1988) Acta Neurochir Suppl. (Wein) 43:193-197. Of these liquid embolics, cyanoacrylate glues are the only liquid embolics currently available to neurosurgeons. However, chronic inflammation is typically seen with cyanoacrylate. treatments (Herrera et al. (1999) Neurol Med Chir (Tokyo) 39(2):134-139) and the degradation product, formaldehyde, is highly toxic to the neighboring tissues. See, Vinters et al (1995) Neuroradiology 27:279-291. Another disadvantage of cyanoacrylate materials is that the polymer will adhere both to the blood vessel and to the tip of the catheter. Thus physicians must retract the catheter immediately after injection of the cyanoacrylate embolic material or risk adhesion of the cyanoacrylate and the catheter to the vessel.
Another class of liquid embolic materials--precipitative materials--was invented in late 80""s. See, Sugawara et al (1993) Neuro Med Chir (Tokyo) 33:71-76; Taki et al (1990) AJNR 11:163-168; Mandai et al (1992) J Neurosurgery 77:497-500. Unlike cyanoacrylate glues which are monomeric and rapidly polymerize upon contact with blood, precipitative materials are pre-polymerized chains that precipitate into an aggregate upon contact with blood. One potential problem in using the precipitating polymers is the use of organic solvents to dissolve the polymers, i.e., ethanol for PVAc and DMSO for EVAL and CA. These materials are strong organic solvents that can dissolve the catheter hub, and, in the case of DMSO, can damage microcapillary vessels and surrounding tissues. These solvents are also known to cause vasospasm of blood vessels. Additionally, these precipitating agents are often difficult to deliver and typically require the use of multi-lumen catheters (see, e.g., U.S. Pat. No. 6,146,373).
U.S. Pat. No. 6,015,424 describes a vascular embolization device comprising an elongate filamentous element that is control lably transformable from a soft, compliant state to a rigid or semi-rigid state after deployment, for example by contact with blood.
None of the currently available devices approximates the design and functional characteristics of the device described below.
Thus, this invention includes novel occlusive compositions as well as methods of using and making these compositions.
In one aspect, the invention includes a vaso-occlusive assembly, comprising (a) an implantable device having an axial lumen and (b) a liquid agent, wherein the liquid agent is infused into the lumen of the implantable device, and further wherein the liquid agent (i) self-polymerizes into a rigid or semi-rigid state after infusion (e.g., over a period of minutes to hours) or (ii) polymerizes upon interaction with one or more additional agents disposed in the lumen of the implantable device. The liquid agent can be any suitable substance, for example, fibrin, fibrinogen, thrombin, collagen, polyethylene glycol, cyanoacrylate, microcrystalline wax compositions, cellulose acetate polymers, plasticizers and combinations of two or more of these materials. The liquid agent can be infused into the lumen of the implantable device after deployment of the device or, alternatively, can be infused into the lumen of the device prior to deployment. Further, the implantable device can be a vaso-occlusive coil or other device.
In certain embodiments, the liquid agent self-polymerizes over a period of minutes to hours. In other embodiments, the liquid agent polymerizes to a rigid or semirigid state upon contact with the one or more additional elements, for example, thrombin or calcium. The additional element required for polymerization can be disposed within the axial lumen prior to deployment or, alternatively, after deployment. Any of the assemblies described herein can further comprise a flexible tubular pusher operably linked to the lumen of the device and/or a radio-opaque material. The radio-opaque material can be integrated into, the device and/or into the liquid agent, additional element or any combination thereof.
In another aspect, the invention includes a vaso-occlusive assembly, comprising (a) an implantable device comprising a polymeric material and (b) a liquid agent capable of at least partially solvating the polymeric material of the implantable device. In certain embodiments, the liquid agent is at least partially miscible with blood. In any of these aspects, the assembly can further include a radio-opaque material in the implantable device and/or in the liquid agent. The radio-opaque material is preferably at least partially miscible with blood and at least partially miscible with the liquid agent.
Any suitable polymeric material can be used for the implantable device, for example, polyesters, polyethers, polyamides, polyfluorocarbons, polyethyleneterephthalate, polyurethanes, polyacrylics, polyvinyl acetate, cellulose acetate, polyvinyl alcohols, polylactide, polyglycolide, poly(lactide-co-glycolide), poly(e-caprolactone), poly(p-dioxanone), poly(lactide-co-trimethylene carbonate), polyhydroxybutyrate, polyhydroxyvalerate, polyanhydrides, polyortoesters or combinations of one or more of these materials. In certain embodiments, the polymeric material is coated onto the surface of the implantable device.
In any of the assemblies described herein, the liquid agent can be, for example, propylene glycol, polyethylene glycols, ethanol, dimethyl sulfoxide, N-methyl-2-pyrrolidone, glycoflirol, Solketal, glycerol formal, acetone, tetrahydrofurfuryl alcohol, diglyme, dimethyl isosorbide, ethyl lactate or combinations thereof.
Methods of occluding a body cavity comprising introducing any of the assemblies described herein also form an aspect of the invention. In certain embodiments, the liquid agent is infused after deployment of the implantable device. In other embodiments, the liquid agent is infused prior to deployment of the implantable device. In embodiments in which the liquid agent comprises a solvating agent, the methods can serve to fuse the implantable device to itself or to one or more additional devices upon re-solidification of the solvated polymeric material.
These and other embodiments of the subject invention will readily occur to those of skill in the art in light of the disclosure herein.